Synthesis and structure-activity relationships of 7- diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine

Article abstract of DOI:10.1021/jm00082a001

A series of novel 6-fluoro-7-diazabicycloalkylquinolonecarboxylic acids substituted with various C₈ (H, F, Cl, N) and N₁ (ethyl, cyclopropyl, vinyl, 2-fluoroethyl, 4-fluorophenyl, 2,4-difluorophenyl) substituents, as well as, 9-fluoro-10-diazabicycloalkylpyridobenzoxazinecarboxylic acids, were prepared and evaluated for antibacterial activity against a range of important veterinary pathogenic bacteria. The diazabicycloalkyl side chains investigated at the 7-position (benzoxazine 10-position) include (1S,4S)-5- methyl-2,5-diazabicyclo[2.2.1]heptane (2), (1S,4S)-2,5- diazabicyclo[2.2.1]heptane (3), (1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptane (4), 8-methyl-3,8-diazabicyclo[3.2.1]octane (5), 9-methyl-3,9-diazabicyclo[4.2.1]nonane (6), 1,4-diazabicyclo[3.2.2]nonane (7), 1,4-diazabicyclo[3.3.1]nonane (8), and 9-methyl-3,9- diazabicyclo[3.3.1]nonane (9). Among these side chains, in vitro potency was not highly variable; other properties therefore proved more critical to the selection of possible development candidates. However, the relative potencies observed for several of these compounds in mouse, swine, and cattle infection models correlated well with those seen in vitro. A combination of the N₁ cyclopropyl group and the C₇ (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2- yl appendage conferred the best overall antibacterial, physiochemical, and pharmacodynamic properties. Hence, danofloxacin (Advocin, 2c) (originally CP- 76,136, 1-cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) was selected as a candidate for development as a therapeutic antibacterial agent for veterinary medicine.